Chewable decongestant compositions

ABSTRACT

The present invention relates to immediate release compositions comprising a pre-complex comprising a polymeric polycarboxylate and an aminophenylalkanol vasoconstrictor in a solid chewable matrix of pharmaceutically-acceptable carrier ingredients wherein the aminophenylalkanol vasoconstrictor and polymeric polycarboxylate are in a weight ratio of from about 5:1 to about 1:10 and wherein the pre-complex is dissociable at a pH of from about 4.5 to about 6.8, releasing the aminophenylalkanol vasoconstrictor.

FIELD OF THE INVENTION

This invention relates to an oral decongestant composition. Inparticular, it relates to an oral decongestant composition in solid,chewable form having improved absorption characteristics and higherpatient compliance. In addition, the invention relates to methods forpreparing such a composition.

BACKGROUND OF THE INVENTION

Pharmaceuticals for oral ingestion can take many different forms, suchas liquids, emulsions, suspensions, aerosol sprays, solid capsules ortablets. Many pharmaceutical compositions including oral decongestantscontain unpalatable ingredients and are therefore marketed in the formof liquids and sprays. Pharmaceutical compositions in the form oftablets or capsules which are intended to be swallowed whole are alsowidely marketed. Taste-masking of the active ingredients contained insuch products can be effected by covering the tablet with a thin andquickly dissolving coating, for example, using a gelatin outer shell inorder to retain the active ingredient until the tablet has beenswallowed. Alternatively, the tablet can be compressed sufficiently sothat it stays intact for the short time that it is in the mouth.

It would be desirable to provide solid, chewable and lozenge forms ofdosage. These are preferred by people who do not like or have difficultyswallowing tablets or capsules, particularly children and older people.Furthermore, solid, chewable tablets have higher patient compliance thanliquids since they are more convenient to carry around. Frequently thebitter taste of pharmaceutically-active ingredients has been masked sothat such drugs can be adapted into acceptable-tasting chewable andlozenge forms.

The concept of providing pharmaceuticals in solid, chewable form hasbeen disclosed in EP-A-0,459,695, where the chewable tablets are madefrom coated granules of medicament. The coating on these granulescomprises a blend of cellulose acetate and/or cellulose acetate butyrateand hydroxypropyl cellulose and provides taste-masking of the activeingredient and sustained-release of the medicament.

EP-A-0,284,408 also discloses a chewable tablet comprising acontrolled-release drug in which granules are coated with a polymer orcopolymer of alkyl esters of acrylic and methacrylic acids and ethylcellulose.

GB-A-2,166,651 relates to a controlled-release powder consisting ofdiscrete microparticles for use in edible pharmaceutical compositions.The particles contain an active ingredient and optionally an excipientin intimate admixture with at least one non-toxic polymer. Each of theparticles are in the form of a micromatrix with active ingredient andthe excipient, if present, uniformly distributed throughout the matrix.These particles have an average size of between 0.1 and 125 μm.

EP-A-0,212,641 discloses a porous drug-polymer matrix with an amino- oramido- containing drug such as dimenhydrinate or salt thereof as theactive ingredient and a pharmaceutically-acceptable copolymer having aplurality of carboxylic acid and ester groups wherein the matrixdissociates in a media having a pH of less than 4, thereby releasing theactive ingredient into the acidic media of the stomach.

U.S. Pat. No. 3,629,392 discloses an aqueous latex of a polymer havingacidic and/or basic groups in contact with a drug also having basicand/or acidic groups. The water is then removed and the productformulated into a suitable dosage form. An aqueous "latex" herein meansan aqueous dispersion of colloidal or near colloidal particles.

U.S. Pat. No. 3,515,781 discloses a capsule containing menthol, thymoland an oral decongestant and which dissolves in the mouth to releasethese substances for the alleviation of the symptoms of nasalcongestion.

While there has been a number of proposals in the art for providing oraldecongestants and other orally-ingestible pharmaceuticals in chewable,sustained- or controlled-release tablet form, there has apparently beenno disclosure of an oral decongestant composition in solid, chewabledosage form which allows for fast release of the decongestant, togetherwith improved taste and consumer acceptability.

Accordingly, the present invention provides a chewable oral decongestantcomposition having enhanced release characteristics combined withimproved taste and consumer acceptability.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, there is provided anoral decongestant composition comprising an aminophenylalkanolvasoconstrictor in a solid chewable matrix ofpharmaceutically-acceptable carrier ingredients, and wherein theaminophenylalkanol vasoconstrictor is present in the form of apre-complex with a polymeric polycarboxylate, the pre-complex comprisingthe aminophenylalkanol vasoconstrictor and polymeric polycarboxylate ina weight ratio of from about 5:1 to about 1:10 and being dissociatablein aqueous media having a pH of between about 4.5 and about 6.8, withrelease of the aminophenylalkanol vasoconstrictor.

The oral decongestant composition of the present invention can be formedby dissolving the aminophenylalkanol vasoconstrictor with thepharmaceutically-acceptable polymeric polycarboxylate in an organicsolvent or aqueous organic solvent mixture and thereafter removing thesolvent to form the aminophenylalkanol vasoconstrictor pre-complex.Thereafter the pre-complex and pharmaceutically-acceptable carrieringredients are admixed and optionally tableted to yield the oraldecongestant composition in solid chewable form. The oral decongestantcomposition of the present invention can also be formed by a methodwherein the aminophenylalkanol vasoconstrictor is in salt form, andwherein the method comprises reducing the particle size of theaminophenylalkanol vasoconstrictor to less than about 300 μm, admixingthe pharmaceutically-acceptable polymeric polycarboxylate and water toform a slurry, followed by adding a stoichiometric amount of sodiumhydroxide solution to the slurry with increased mixing and thereafterdrying the aminophenylalkanol vasoconstrictor pre-complex. Again thepre-complex and pharmaceutically-acceptable carrier ingredients areadmixed and optionally tableted to give the oral decongestant in solidchewable tablet form. The oral decongestant of the present invention ischewable to initiate release of the active ingredient in the mouth andsubsequently in the stomach/intestine.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention a solid, chewable tablet isformed comprising an aminophenyl C₂ -C₃ alkanol vasoconstrictor as anoral decongestant and wherein the aminophenyl C₂ -C₃ alkanolvasoconstrictor is in the form of a pre-complex with the polymericpolycarboxylate. The polymeric polycarboxylate is chosen such that thepre-complex is dissociatable in water or aqueous media at a pH at leastin the range from about 4.5 to about 6.8, with release of theaminophenyl C₂ -C₃ alkanol vasoconstrictor. The aminophenylpropanolvasoconstrictor can be selected from 2-amino-1-phenyl-1-C₂ -C₃ alkanols,N-C₁ -C₄ alkyl derivatives, salts and mixtures thereof. Optionally, thephenyl moiety of the 2-amino-1-phenyl-1-C₂ -C₃ alkanol can besubstituted by one or more hydroxy groups. In preferred embodiments ofthe invention the aminophenyl C₂ -C₃ alkanol vasoconstrictor is selectedfrom pseudoephedrine and phenylpropanolamine. Other suitable aminophenylC₂ -C₃ alkanols include phenylephrine and phenylethanolamine. Thepharmaceutically-acceptable copolymer component of the composition ofthe present invention is preferably a polymeric polycarboxylatecomprising methacrylic acid and methyl methacrylate. Such polymericpolycarboxylates are capable of interacting with the aminophenyl C₂ -C₃alkanol vasoconstrictor to bring about effective taste-masking of thebitter tasting active material. Preferred polycarboxylates for use inthe present invention are commercially available under the trade nameEudragit-L-100 (trade mark of R ohm Pharma).

The aminophenyl C₂ -C₃ alkanol vasoconstrictor has an amine group whichis capable of interacting with the carboxylic acid groups of thecopolymer, to form a pre-complex by, for example, hydrogen bonding, saltformation or ion-pair formation.

The pre-complex can be prepared by dissolving aminophenyl C₂ -C₃ alkanolvasoconstrictor with the pharmaceutically-acceptable copolymer in analcoholic or aqueous alcoholic solution comprising from 1 to 4 carbonatoms, for example, ethanol. The solvent can be removed by any one of anumber of methods including evaporation under vacuum, spray drying, traydrying, drum or belt film drying. The preferred method of solventremoval in the present invention is by evaporation under vacuum atelevated temperatures, preferably at least about 30° C.

An additional method for preparing the pre-complex comprises reducingthe particle size of the aminophenyl C₂ -C₃ alkanol vasoconstrictor toless than about 300 μm, the aminophenyl C₂ -C₃ alkanol vasoconstrictorbeing in salt form, admixing the pharmaceutically-acceptable polymericpolycarboxylate and water to form a slurry, followed by adding astoichiometric amount of sodium hydroxide solution to the slurry withincreased mixing and thereafter drying the aminophenylalkanolvasoconstrictor pre-complex. A number of methods can be used herein fordrying the pre-complex selected from evaporation under vacuum, spraydrying, tray drying, drum or belt film drying. The preferred method ofdrying the pre-complex prepared by this method is by evaporation undervacuum at elevated temperatures, preferably at least about 60° C.

The oral decongestant composition of the present invention preferablycomprises from about 1% to about 15%, more preferably from about 2% toabout 10%, by weight thereof of aminophenyl C₂ -C₃ alkanolvasoconstrictor and from about 1% to about 30%, more preferably fromabout 5% to about 20% by weight thereof of the copolymer. In preferredembodiments the monomer ratio of methacrylic acid to methyl methacrylateis from about 3:1 to about 2:3.

The composition of the invention comprises the aminophenyl C₂ -C₃alkanol vasoconstrictor pre-complex within a solid chewable matrix ofpharmaceutically-acceptable carrier ingredients. Suitable carrieringredients can be selected from sugars, sugar substitutes, and mixturesthereof. The sugars or sugar substitutes can be selected from Talin,sucrose, glucose, fructose, high fructose corn syrup, invert sugar,mannitol, sorbitol and mixtures thereof. In preferred embodiments, thematrix of carrier ingredients and the aminophenyl C₂ -C₃ alkanolvasoconstrictor pre-complex are in a weight ratio in the range of fromabout 1:1 to about 50:1, preferably from about 1:10 to about 30:1. Thematrix can additionally comprise conventional colouring agents, fillersand plasticizers, flavouring agents, colouring agents and/or artificialsweetening agents. Suitable artificial sweeteners can be selected fromaspartame, cyclamate, saccharin, Acesulfame™ K and mixtures thereof.

Suitable flavouring agents include an aromatic flavouring agent selectedfrom menthol, peppermint oil, camphor, eucalyptol, eucalyptus oil,preferably menthol. It is a feature of the invention that the additionof the aromatic flavouring agent in combination with theaminophenylpropanol vasoconstrictor pre-complex is especially valuablefor providing improved decongestant release characteristics and patientcompliance.

According to another aspect of the invention, there is provided an oraldecongestant composition comprising an aromatic flavouring agenttogether with an aminophenyl C₂ -C₃ alkanol vasoconstrictor in a solidchewable matrix of pharmaceutically-acceptable carrier ingredients, andwherein the aminophenyl C₂ -C₃ alkanol vasoconstrictor is present in theform of a pre-complex with a polymeric polycarboxylate, the pre-complexcomprising the aminophenyl C₂ -C₃ alkanol vasoconstrictor and polymericpolycarboxylate in a weight ratio of from about 5:1 to about 1:10 andbeing dissociatable in a media having a pH in the range from about 4.5to about 6.8, with release of the aminophenyl C₂ -C₃ alkanolvasoconstrictor.

The compositions of the present invention can be provided in variousforms, for example, solid chewable tablets, capsules and lozenges. Theamount of the aminophenyl C₂ -C₃ alkanol vasoconstrictor pre-complexpresent per unit dose of the final composition is from about 50 mg toabout 500 mg, preferably from about 70 mg to about 250 mg. The amount ofaminophenyl C₂ -C₃ alkanol vasoconstrictor per unit dose of the finalcomposition, on the other hand, is preferably from about 20 mg to about250 mg, especially from about 40 mg to about 150 mg.

The present invention is illustrated by the following examples.

EXAMPLE 1

An oral decongestant composition of the invention is prepared asfollows. 25 g of pseudoephedrine hydrochloride salt is dissolved inabout 25 g water. A stoichiometric amount of a 10% sodium hydroxidesolution is added to the solution to precipitate pseudoephedrine in theform of a slurry. 50 g of Eudragit-L-100 polymer is added to the slurrywith mixing. About 25 g of ethanol is added to the mixture in order tosolubilize the polymer and complete the drug-polymer interaction. Themixture is dried under vacuum at about 55° C. and is then granulated bypassing it through a 177 μm sieve (mesh #80). The pseudoephedrinspre-complex thus prepared is then incorporated in a tablet-form oraldecongestant composition as follows:

10 mg of aspartame and 10 mg of finely powdered menthol are mixed with180 mg of the drug-polymer complex. 250 mg of mannitol and 25 mg ofaspartame are added, followed by admixing of 515 mg of sorbitol. 10 mgof magnesium stearate is then added as a lubricant and the tablets arecompressed at a pressure of 3 metric tons.

EXAMPLE 2

A second oral decongestant is prepared as follows:

50 g of pseudoephedrine hydrochloride is ground to give a particle sizeof less than about 300 μm and then mixed thoroughly with 100 g ofEudragit L-100. 120 ml of water is added with mixing to form a slurry. Astoichiometric amount of 10% sodium hydroxide solution is added to theslurry with increased mixing. The mixture is dried under vacuum at about60° C. and is then passed through a 300 μm sieve to obtain thepseudoephedrine pre-complex in granulated form. The pseudoephedrinepre-complex is then incorporated in a tablet-form oral decongestantcomposition as follows:

200 mg of pseudoephedrine pre-complex is ground and passed through a 300μm sieve. 10 mg each of aspartame and finely powdered menthol is thenmixed with the pseudoephedrine pre-complex. 250 mg of mannitol is addedalong with 25 mg of aspartame, followed by admixing of 500 mg ofsorbitol. Addition of 10 mg of magnesium stearate is followed bycompression of the mixture at a pressure of 3 metric tons to formtablets.

The oral decongestants of Examples 1 and 2 demonstrate improvedabsorption characteristics together with higher patient compliance.

We claim:
 1. An oral decongestant composition comprising anaminophenylalkanol vasoconstrictor in a solid chewable matrix ofpharmaceutically-acceptable carrier ingredients, and wherein theaminophenylalkanol vasoconstrictor is present in the form of apre-complex with a polymeric polycarboxylate consisting of methacrylicacid and methyl methacrylate, the pre-complex comprising theaminophenylalkanol vasoconstrictor and the polymeric polycarboxylate ina weight ratio of from about 5:1 to about 1:10 and being dissociable inaqueous media having a pH of between about 4.5 to about 6.8, withrelease of the aminophenylalkanol vasoconstrictor.
 2. An oraldecongestant composition according to claim 1 wherein theaminophenylalkanol vasoconstrictor is selected from the group consistingof 2-amino-1-phenyl-1-ethanols, 2-amino-1-phenyl-1-propanols,2-methylamino-1-phenyl-1-alkanols, 2-ethylamino-1-phenyl-1-alkanols,2-propylamino-1-phenyl-1-alkanols, 2-butylamino-1-phenyl-1-alkanols,pharmaceutically acceptable salts, and mixtures thereof.
 3. An oraldecongestant composition according to claim 2 wherein theaminophenylalkanol vasoconstrictor is selected from the group consistingof pseudoephedrine, phenylephrine or phenylpropanolamine and mixturesthereof.
 4. An oral decongestant composition according to claim 1 whichcomprises:a) from about 1% to about 15% by weight of composition of theaminophenylalkanol vasoconstrictor, and b) from about 1% to about 30% byweight of composition of the polymeric polycarboxylate.
 5. An oraldecongestant composition according to claim 4 wherein the copolymercomprises methacrylic acid and methyl methacrylate in a monomer ratio offrom about 3:1 to about 2:3.
 6. An oral decongestant compositionaccording to claim 1 wherein the matrix of carrier ingredients comprisesone or more materials selected from the group consisting of sugars,sugar substitutes, and mixtures thereof.
 7. An oral decongestantcomposition according to claim 6 wherein the sugar or sugar substituteis selected from the group consisting of Talin, sucrose, glucose,fructose, high fructose corn syrup, invert sugar, mannitol, sorbitol andmixtures thereof.
 8. An oral decongestant composition according to claim1 wherein the matrix of carrier ingredients additionally comprises oneor more plasticizers, fillers, flavouring agents, colouring agentsand/or artificial sweetening agents.
 9. An oral decongestant compositionaccording to claim 8 wherein the artificial sweetening agent is selectedfrom the group consisting of aspartame, cyclamate, saccharin, acesulfameK and mixtures thereof.
 10. An oral decongestant composition accordingto claim 8 in which the flavouring agent is an aromatic flavouringagent.
 11. A method for producing the pre-complex of the oraldecongestant composition according to claim 1 comprising dissolving theaminophenylalkanol vasoconstrictor with the pharmaceutically-acceptablepolymeric polycarboxylate in an organic solvent or aqueous organicsolvent mixture and thereafter removing the solvent to form theaminophenylalkanol vasoconstrictor pre-complex.
 12. A method accordingto claim 11 wherein the solvent is removed under vacuum at a temperatureof at least about 30° C.
 13. A method according to claim 12 wherein thesolvent is a lower alcohol comprising from 1 to 4 carbon atoms.
 14. Amethod for producing the pre-complex of the oral decongestantcomposition according to claim 1 wherein the aminophenylalkanolvasoconstrictor is in salt form and wherein the method comprisesreducing the particle size of the aminophenylalkanol vasoconstrictor toless than about 300 μm, admixing the pharmaceutically-acceptablepolymeric polycarboxylate and water to form a slurry, followed by addinga stoichiometric amount of sodium hydroxide solution to the slurry withincreased mixing and thereafter drying the aminophenylalkanolvasoconstrictor pre-complex.
 15. A method according to claim 14 whereinthe aminophenylalkanol vasoconstrictor pre-complex is dried under vacuumat a temperature of about 60° C.
 16. An oral decongestant compositionaccording to claim 2 wherein the phenyl moiety of the aminophenylalkanolcontains at least one hydroxy group.
 17. An oral decongestantcomposition according to claim 10 wherein the aromatic flavouring agentis menthol.